Essential and non-overlapping IL-2Rα-dependent processes for thymic development and peripheral homeostasis of regulatory T cells

• Published in: Nature communications 2019-03, Vol.10 (1), p.1037-1037, Article 1037
• Main Authors: Toomer, Kevin H., Lui, Jen Bon, Altman, Norman H., Ban, Yuguang, Chen, Xi, Malek, Thomas R.
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 38; 38/39; 631/250/127/1213; 631/250/1619/554/1898/1271; 631/250/2502; 631/250/38; 96/2; Animals; Apoptosis; Biosynthetic Pathways; CD25 antigen; Cholesterol; Clonal deletion; Cytokines - metabolism; Female; Homeostasis; Humanities and Social Sciences; Immunoregulation; Interleukin 2; Interleukin 2 receptors; Interleukin-2 Receptor alpha Subunit - genetics; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukin-2 Receptor beta Subunit - metabolism; Lipids; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; multidisciplinary; Organogenesis; Oxidative Stress; Phenotype; Science; Science (multidisciplinary); Signal Transduction; Signaling; Skin - pathology; Stability; Survival; T-Lymphocytes, Regulatory - metabolism; Thymus; Thymus Gland - growth & development; Thymus Gland - immunology; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08960-1

IL-2R signaling is essential for regulatory T cell (Treg) function. However, the precise contribution of IL-2 during Treg thymic development, peripheral homeostasis and lineage stability remains unclear. Here we show that IL-2R signaling is required by thymic Tregs at an early step for expansion and survival, and a later step for functional maturation. Using inducible, conditional deletion of CD25 in peripheral Tregs, we also find that IL-2R signaling is indispensable for Treg homeostasis, whereas Treg lineage stability is largely IL-2-independent. CD25 knockout peripheral Tregs have increased apoptosis, oxidative stress, signs of mitochondrial dysfunction, and reduced transcription of key enzymes of lipid and cholesterol biosynthetic pathways. A divergent IL-2R transcriptional signature is noted for thymic Tregs versus peripheral Tregs. These data indicate that IL-2R signaling in the thymus and the periphery leads to distinctive effects on Treg function, while peripheral Treg survival depends on a non-conventional mechanism of metabolic regulation. Interleukin-2 (IL-2) signaling is required for regulatory T (Treg) cell differentiation in the thymus, but its function in peripheral Tregs is still unclear. Here the authors show, using inducible deletion of IL-2 receptor subunit CD25, that IL-2 signaling is essential for maintaining peripheral Treg homeostasis, but dispensable for lineage stability.